Pilot multi-centre randomised trial of the impact of pre-operative focused cardiac ultrasound on mortality and morbidity in patients having surgery for femoral neck fractures (ECHONOF-2 pilot).

Hip fracture surgery is common, usually occurs in elderly patients who have multiple comorbidities, and is associated with high morbidity and mortality. Pre-operative focused cardiac ultrasound can alter diagnosis and management, but its impact on outcome remains uncertain. This pilot study assessed feasibility and group separation for a proposed large randomised clinical trial of the impact of pre-operative focused cardiac ultrasound on patient outcome after hip fracture surgery. Adult patients requiring hip fracture surgery in four teaching hospitals in Australia were randomly allocated to receive focused cardiac ultrasound before surgery or not. The primary composite outcome was any death, acute kidney injury, non-fatal myocardial infarction, cerebrovascular accident, pulmonary embolism or cardiopulmonary arrest within 30 days of surgery. Of the 175 patients screened, 100 were included as trial participants (screening:recruitment ratio 1.7:1), 49 in the ultrasound group and 51 as controls. There was one protocol failure among those recruited. The primary composite outcome occurred in seven of the ultrasound group patients and 12 of the control group patients (relative group separation 39%). Death, acute kidney injury and cerebrovascular accident were recorded, but no cases of myocardial infarction, pulmonary embolism or cardiopulmonary arrest ocurred. Focused cardiac ultrasound altered the management of 17 participants, suggesting an effect mechanism. This pilot study demonstrated that enrolment and the protocol are feasible, that the primary composite outcome is appropriate, and that there is a treatment effect favouring focused cardiac ultrasound - and therefore supports a large randomised clinical trial.

The effect of intensive care unit admission on smokers' attitudes and their likelihood of quitting smoking.

We sought to estimate the proportion of patients admitted to a metropolitan intensive care unit (ICU) who were current smokers, and the relationships between ICU survivors who smoked and smoking cessation and/or reduction six months post-ICU discharge. We conducted a prospective cohort study at a metropolitan level III ICU in Melbourne, Victoria. One hundred consecutive patients who met the inclusion criteria were included in the study. Inclusion criteria consisted of patients who were smokers at time of ICU admission, had an ICU length of stay greater than one day, survived to ICU discharge, and provided written informed consent. A purpose-designed questionnaire which included the Fagerstrom test for nicotine dependence and evaluation of patients' attitude towards smoking cessation was completed by participants following ICU discharge and prior to hospital discharge. Participants were re-interviewed over the phone at six months post-ICU discharge. Of the 1,062 patients admitted to ICU, 253 (23%) were current smokers and 100 were enrolled. Six months post-ICU discharge, 28 (33%) of the 86 participants who were alive and contactable had quit smoking and 35 (41%) had reduced smoking. The median number of reported cigarettes smoked per day reduced by 40%. Participants who initially believed their ICU admission was smoking-related were more likely to have quit six months post-ICU discharge (odds ratio 2.98; 95% confidence interval 1.07 to 8.26; P=0.036). Six months post-ICU discharge, 63/86 (74%) of participants had quit or reduced their smoking. Further research into targeted smoking cessation counselling for ICU survivors is indicated.

Small-Molecule Targeting of BET Proteins in Cancer.

BET proteins have recently become recognized for their role in a broad range of cancers and are defined by the presence of two acetyl-histone reading bromodomains and an ET domain. This family of proteins includes BRD2, BRD3, BRD4, and BRDT. BRD4 is the most-studied BET protein in cancer, and normally serves as an epigenetic reader that links active chromatin marks to transcriptional elongation through activation of RNA polymerase II. The role of BRD3 and BRD4 first became known in cancer as mutant oncoproteins fused to the p300-recruiting NUT protein in a rare aggressive subtype of squamous cell cancer known as NUT midline carcinoma (NMC). BET inhibitors are acetyl-histone mimetics that specifically bind BET bromodomains, competitively inhibiting its engagement with chromatin. The antineoplastic effects of BET inhibitors were first demonstrated in NMC and have since been shown to be effective at inhibiting the growth of many different cancers, particularly acute leukemia. BET inhibitors have also been instrumental as tool compounds that have demonstrated the key role of BRD4 in driving NMC and non-NMC cancer growth. Many clinical trials enrolling patients with hematologic and solid tumors are ongoing, with encouraging preliminary findings. BET proteins BRD2, BRD3, and BRD4 are expressed in nearly all cells of the body, so there are concerns of toxicity with BET inhibitors, as well as the development of resistance. Toxicity and resistance may be overcome by combining BET inhibitors with other targeted inhibitors, or through the use of novel BET inhibitor derivatives.

NUT Carcinoma of the Sublingual Gland.

NUT carcinoma (NC) is a recently described, rare and extremely aggressive cancer primarily located to supradiaphragmatic structures and affecting young individuals. NC is characterized by translocations involving the NUT gene on 15q14 with the most common translocation partner gene being BRD4 on 19p13, resulting in the t(15;19)(q14;p13) karyotype. NC is poorly differentiated and is likely to be overlooked and misdiagnosed as poorly differentiated squamous cell carcinoma (SCC) when immunohistochemical evaluation of NUT protein expression is omitted. Previously, NC has been found in the parotid and submandibular glands and we present the first case in the sublingual gland arising in a 40-year-old woman. We discuss the diagnostic considerations for poorly differentiated carcinomas of the salivary glands and advocate the inclusion of NUT immunohistochemistry in this setting. Not only does the NC diagnosis confer a grave prognosis when treated as SCC as illustrated by the present case, but is important for the inclusion of patients in ongoing clinical trials.

Susceptibility to infection and pathogenicity of White Spot Disease (WSD) in non-model crustacean host taxa from temperate regions.

Despite almost two decades since its discovery, White Spot Disease (WSD) caused by White Spot Syndrome Virus (WSSV) is still considered the most significant known pathogen impacting the sustainability and growth of the global penaeid shrimp farming industry. Although most commonly associated with penaeid shrimp farmed in tropical regions, the virus is also able to infect, cause disease and kill a wide range of other decapod crustacean hosts from temperate regions, including lobsters, crabs, crayfish and shrimp. For this reason, WSSV has recently been listed in European Community Council Directive 2006/88. Using principles laid down by the European Food Safety Authority (EFSA) we applied an array of diagnostic approaches to provide a definitive statement on the susceptibility to White Spot Syndrome Virus (WSSV) infection in seven ecologically or economically important crustacean species from Europe. We chose four marine species: Cancer pagurus, Homarus gammarus, Nephrops norvegicus and Carcinus maenas; one estuarine species, Eriocheir sinensis and two freshwater species, Austropotamobius pallipes and Pacifastacus leniusculus. Exposure trials based upon natural (feeding) and artificial (intra-muscular injection) routes of exposure to WSSV revealed universal susceptibility to WSSV infection in these hosts. However, the relative degree of susceptibility (measured by progression of infection to disease, and mortality) varied significantly between host species. In some instances (Type 1 hosts), pathogenesis mimicked that observed in penaeid shrimp hosts whereas in other examples (Types 2 and 3 hosts), infection did not readily progress to disease, even though hosts were considered as infected and susceptible according to accepted principles. Results arising from challenge studies are discussed in relation to the potential risk posed to non-target hosts by the inadvertent introduction of WSSV to European waters via trade. Furthermore, we highlight the potential for susceptible but relatively resistant hosts to serve as models to investigate natural mitigation strategies against WSSV in these hosts. We speculate that these non-model hosts may offer a unique insight into viral handling in crustaceans.

BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells.

An unusual group of carcinomas, here termed nuclear protein in testis (NUT) midline carcinomas (NMC), are characterized by translocations that involve NUT, a novel gene on chromosome 15. In about 2/3rds of cases, NUT is fused to BRD4 on chromosome 19. Using a candidate gene approach, we identified two NMCs harboring novel rearrangements that result in the fusion of NUT to BRD3 on chromosome 9. The BRD3-NUT fusion gene encodes a protein composed of two tandem chromatin-binding bromodomains, an extra-terminal domain, a bipartite nuclear localization sequence, and almost the entirety of NUT that is highly homologous to BRD4-NUT. The function of NUT is unknown, but here we show that NUT contains nuclear localization and export sequences that promote nuclear-cytoplasmic shuttling via a leptomycin-sensitive pathway. In contrast, BRD3-NUT and BRD4-NUT are strictly nuclear, implying that the BRD moiety retains NUT in the nucleus via interactions with chromatin. Consistent with this idea, FRAP studies show that BRD4, BRD4-NUT and BRD3-NUT have significantly slower rates of lateral nuclear diffusion than that of NUT. To investigate the functional role of BRD-NUT fusion proteins in NMCs, we investigated the effects of siRNA-induced BRD3-NUT and BRD4-NUT withdrawal. Silencing of these proteins in NMC cell lines resulted in squamous differentiation and cell cycle arrest. Together, these data suggest that BRD-NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation.

Nicotiana occidentalis: A New Herbaceous Host for Blueberry scorch virus.

Blueberry scorch virus(BlScV) is a carlavirus that causes a serious disease of blueberries (Vaccinium corymbosum L.) in North America (2). In aphid-transmission studies of BlScV using blueberry as host and test species, we found the rate of transmission to be low, and a lengthy incubation period was required before BlScV could be detected. For sequencing studies, RNA extraction from blueberry using standard methods was unreliable and inefficient. These problems prompted a search for alternate hosts. Of 12 herbaceous hosts screened for BlScV transmission using the blueberry aphid, Ericaphis fimbriata Richards, with mechanical transmission, only Nicotiana occidentalis (Wheeler) became infected. After 3 to 4 weeks, infection of N. occidentalis with BlScV resulted in mild symptoms that included pronounced leaf twisting and swollen leaf veins. Infection with BlScV was confirmed using a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) kit (Agdia Inc., Elkhart, IN), polyclonal antibodies to BlScV from the antiserum collection at the Pacific Agri-Food Research Center, Summerland, British Columbia, Canada, and reverse transcription-polymerase chain reaction (RT-PCR). Forward (5'-NTAAACACTCCCGAATATAC-3') and reverse (5'-CAGATTGCTTATCCGGCTTC-3') primers were designed with the published sequence of BlScV isolate NJ-02 (GenBank Accession No. NC003499). An amplicon of the expected size was generated and sequenced. BLAST analysis indicated that the nucleotide sequence of the amplified fragment was 87% identical to the corresponding sequence in NJ-02 (1). N. occidentalis was readily infected with BlScV following aphid or mechanical inoculations from blueberry. With E. fimbriata as the aphid vector, the transmission rate from blueberry to N. occidentalis was approximately 26%, compared with 70% for mechanical inoculations. Mechanical transfer of BlScV between infected N. occidentalisplants resulted in a 100% transmission rate. Recently, with N. occidentalis, we have completely sequenced two strains of BlScV from British Columbia, Canada and identified several aphid vector species. The identification of N. occidentalis as an herbaceous host of BlScV greatly facilitates future studies on the virus. References: (1) T. D. Cavileer et al. J. Gen. Virol. 75: 711, 1994. (2) R. R. Martin and P. R. Bristow. Phytopathology 78:1636, 1988.

Screening for physical and psychological illness in the British Armed Forces: I: The acceptability of the programme.

OBJECTIVES: To assess the response to a self-administered questionnaire and attendance of a medical centre for physical and psychological health screening. METHODS: 4500 men and women from the three services were randomly selected to receive either a full or abridged screening questionnaire. The full questionnaire included the General Health Questionnaire-12 (GHQ-12) and Post-traumatic Stress Disorder (PTSD) checklist, 15 symptoms, a self-assessed health status question and three questions on alcohol behaviour (WHO Audit). The abridged questionnaire included GHQ-4, a slightly shortened PTSD checklist and five symptoms, but excluded questions on alcohol behaviour. All 'screen-positive' and a random 'screen-negative' sample were invited to attend a medical centre. RESULTS: 67.1% of the servicemen completed a questionnaire; slightly but significantly more the abridged than the full questionnaire (4.9%, 95% confidence interval 2.3-7.4%). Of those receiving a full or abridged questionnaire, 32% and 22.5% respectively were 'screen-positives', most of the difference (7.5%) attributable to alcohol behaviour. Less than 30% of the servicemen invited to attend a medical centre accepted the invitation, even fewer during the preparation for deployment to Iraq. Those who fulfilled the criteria for PTSD, alcohol behaviour or multi-criteria 'screen-positive' were more reluctant than controls to attend. CONCLUSIONS: Screening for psychological illness has little support among servicemen, perhaps because they may not wish to share concerns with a military doctor. Avoidance behaviour among those with a psychological condition may also selectively reduce willingness to attend a medical centre. Screening during pre-deployment periods has even less support than at other times.

Screening for physical and psychological illness in the British Armed Forces: II: Barriers to screening--learning from the opinions of Service personnel.

OBJECTIVE: To identify any potential barriers to the effectiveness of a military health screening programme based on the beliefs of British Service personnel. METHODS: As part of a pilot evaluation of the suitability of a new health screening questionnaire for the British Armed Forces, 73 men and women from the three Services, of various ranks and age, underwent a semi-structured interview after completing a screening questionnaire. Participants were asked about the veracity of their answers and their views regarding a screening questionnaire. Afterwards questionnaires were sent to 4496 randomly selected personnel from the three Services, which validated the main emerging themes. A constant comparative method of analysis was used to identify and categorise all ideas presented. RESULTS: The main barriers to health screening were lack of trust, perceived low quality of healthcare, and perceived lack of concern within the institution about work environments and home life. The central issue was 'confidence' in military health care provision. Screening was considered worthwhile, but many confided that they would not honestly answer some items in the questionnaire. Lack of trust in medical confidentiality, stigmatisation and fears that the process would jeopardise career prospects were stressed. Many Service personnel admitted to seeking medical help outside the Armed Forces. CONCLUSIONS: Concerns raised by Service personnel may endanger the value of a screening programme and the provision of health services. Greater emphasis needs to be placed upon gaining the confidence of those targeted for health screening.

Screening for physical and psychological illness in the British Armed Forces: III: The value of a questionnaire to assist a Medical Officer to decide who needs help.

OBJECTIVES: To estimate the positive and negative predictive values (PPVT and NPVT), sensitivity and specificity of a full and abridged screening questionnaire of physical and psychological health, using primary care doctors' (medical officers [MOs]) assessments as to whether the servicemen needed medical help as a gold standard. METHODS: From a tri-service random sample of those who completed a questionnaire, all 'screen-positive' and an equal random sample of 'screen-negative' were selected to attend their medical centre. MOs were aware that the screening was aimed at detecting psychological illness, but were blind as to the 'screen-positivity' of any serviceman. The MO completed a questionnaire that asked whether the patient needed medical help and whether s/he was previously aware of this need. RESULTS: 314 subjects were available for analysis. The PPVT was 47% (95% confidence interval [CI] 36-59%) for the full questionnaire and 48% (95% CI 36-60%) for the abridged questionnaire. Of those 'screen-positive' subjects whom the MO rated as needing help, one third had problems already known to the MO, regardless of the length of the questionnaire. The sensitivity and specificity of the full and abridged questionnaires were 43% and 74%, and 36% and 83% respectively. The PPVT did not vary greatly between health dimensions nor did selection of servicemen with very high scores. CONCLUSIONS: The use of MOs as a gold standard is important because of their central role in initiating the management of any condition uncovered by a screening programme. Using MOs as a gold standard, the validity of the screening questionnaires for physical and psychological health in the military was mediocre.

Trends in the incidence of bladder cancer in Nova Scotia: a twenty-year perspective.

INTRODUCTION: Bladder cancer is the most common malignant tumor of the urinary system. Tobacco smoking has been implicated as a major risk factor for the development of bladder cancer and Nova Scotia has some of the highest smoking rates in Canada. We examined trends in the incidence of bladder cancer in Nova Scotia between 1980 and 1999. MATERIALS AND METHODS: Data on incident cases of bladder cancer diagnosed in Nova Scotia over a twenty-year period (1980 - 1999) were obtained from the Nova Scotia Cancer Registry. The age- standardized incidence and mortality due to bladder cancer was calculated for both genders. Trends in the incidence of bladder cancer during the study period were analyzed for three different age groups in each gender as an estimate of birth cohort. The average annual percent change (AAPC) in incidence of bladder cancer was calculated. RESULTS: Between 1980 and 1999, 3569 cases of bladder cancer were reported (male: female = 2.9:1). The overall incidence of bladder cancer increased in both males (27.5 to 39.5 cases per 100 000) and females (7.0 to 10.7 cases per 100 000). Mortality rates were stable. There was a trend towards an increase in bladder cancer rates for all age groups analyzed, with a substantial rise occurring in females less than 65 years of age. The AAPC in incidence of bladder cancer was +1.5 for males and +2.6 for females. CONCLUSIONS: We hypothesize that the rising incidence of bladder cancer in Nova Scotia, particularly in individuals less than 65 years of age, is related to changes in cigarette smoking practices during the past century. As the population ages, we are likely to see an increased incidence of bladder cancer in females.

Chronic cough due to gastroesophageal reflux disease: efficacy of antireflux surgery.

BACKGROUND: Gastroesophageal reflux disease (GERD) can be overlooked as the cause of chronic cough (CC) when typical gastrointestinal symptoms are absent or minimal. We analyzed the outcomes of Nissen fundoplication (NF) for patients who failed medical therapy for CC attributable only to GERD (G-CC). We performed a prospective outcome evaluation of 21 consecutive patients with G-CC undergoing NF from 1997 to 2000 at a tertiary care university hospital. MATERIALS AND METHODS: Twenty-one patients without prior antireflux surgeries had G-CC diagnosed by a clinical profile and 24-h pH monitoring showing a cough-reflux correlation. Respiratory symptoms alone were present in 53% of patients. NF was performed when G-CC persisted despite intensive medical therapy, including an antireflux diet. Preoperatively, all patients underwent 24-h pH monitoring, esophageal manometry, barium swallow, gastric emptying study, bronchoscopy, and upper endoscopy. NF was utilized in all cases, laparoscopically in 18. Before and after surgery, patients graded their cough severity using the Adverse Cough Outcome Survey (ACOS). Quality of life was measured using the Sickness Impact Profile (SIP). RESULTS: Postoperatively, 18 patients (86%) reported an improvement of their cough. G-CC considerably improved in 16/21 patients (76%), with complete resolution in 13 patients (62%). Mild to moderate improvement was found in 2 patients (10%). Patient-reported cough severity (ACOS) and quality of life (SIP) both significantly improved early (6-12 weeks) postoperatively and persisted during the long-term (1 year) follow-up. The average hospital length of stay was 1.78 +/- 0.2 (l-4) days for the laparoscopic (n = 18) and 6.3 +/- 1.2 (4-8) days for the open surgery (n = 3) groups. CONCLUSION: Twenty-four-hour esophageal pH monitoring is a valuable tool for preoperative cough-reflux correlation. Antireflux surgery is effective in carefully selected patients whose refractory CC is attributable only to GERD. NF controls the severity of cough while improving the quality of life. Outcomes are further enhanced using laparoscopic procedures with shorter hospital stays.

Molecular circuits, biological switches, and nonlinear dose-response relationships.

Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment.

BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).

Translocation t(15;19)(q13;p13.1) defines a lethal midline carcinoma arising adjacent to respiratory tract in young people. To characterize molecular alterations responsible for the distinctly aggressive biological behavior of this cancer, we mapped the chromosome 15 and 19 translocation breakpoints by fluorescence in situ hybridization (FISH) and Southern blotting. To evaluate preliminarily the frequency, anatomical distribution, and histological features of t(15;19) cancer, we developed a FISH assay for paraffin sections. Our findings reveal a novel oncogenic mechanism in which the chromosome 19 translocation breakpoint interrupts the coding sequence of a bromodomain gene, BRD4. These studies implicate BRD4 as a potential partner in a t(15;19)-associated fusion oncogene. In addition, we localized the chromosome 15 breakpoint to a 9-kb region in each of two cases, thereby identifying several candidate oncogenes which might represent the BRD4 fusion partner. FISH evaluation of 13 pediatric carcinomas revealed t(15;19) in one of four sinonasal carcinomas, whereas this translocation was not detected in thymic (n = 3), mucoepidermoid (n = 3), laryngeal (n = 2), or nasopharyngeal (n = 1) carcinomas. Our studies shed light on the oncogenic mechanism underlying t(15;19) and provide further evidence that this highly lethal cancer arises from respiratory mucosa.

Phytodetoxification of TNT by transgenic plants expressing a bacterial nitroreductase.

There is major international concern over the wide-scale contamination of soil and associated ground water by persistent explosives residues. 2,4,6-Trinitrotoluene (TNT) is one of the most recalcitrant and toxic of all the military explosives. The lack of affordable and effective cleanup technologies for explosives contamination requires the development of better processes. Significant effort has recently been directed toward the use of plants to extract and detoxify TNT. To explore the possibility of overcoming the high phytotoxic effects of TNT, we expressed bacterial nitroreductase in tobacco plants. Nitroreductase catalyzes the reduction of TNT to hydroxyaminodinitrotoluene (HADNT), which is subsequently reduced to aminodinitrotoluene derivatives (ADNTs). Transgenic plants expressing nitroreductase show a striking increase in ability to tolerate, take up, and detoxify TNT. Our work suggests that expression of nitroreductase (NR) in plants suitable for phytoremediation could facilitate the effective cleanup of sites contaminated with high levels of explosives.

Cough and gastroesophageal reflux: identifying cough and assessing the efficacy of cough-modifying agents.

From a symptom research standpoint, much has been learned about the management of cough in general and cough caused by gastroesophageal reflux disease in particular. Yet, before further advances can be made in our understanding of how to best manage patients with this common symptom, methodologic challenges remain to be solved. One of the most basic is the development of valid and reliable methods by which to identify cough, assess its impact on patients, and assess the efficacy of cough therapies. Herein, we review the characteristics of cough that relate to its assessment and how the effect of drug treatment on cough has been assessed. Perspective is provided on evaluating the efficacy of cough-modifying agents and the optimal method for identifying a cough and linking it with a reflux event. Investigators should use both subjective and objective methods, because they have the potential to measure different aspects of cough. Subjective measures, such as a cough-specific quality-of-life instruments, are likely to best reflect the severity of cough from the patient's standpoint, because a subjective response most likely integrates both cough frequency and intensity. The ideal objective method should allow cough to be automatically counted over 24 hours in an ambulatory setting. Although it is theoretically possible to design and construct such a device that is also relatively unobtrusive, reliable, and accurate, one is not yet available.

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

Upper respiratory tract carcinoma with chromosomal translocation 15;19: evidence for a distinct disease entity of young patients with a rapidly fatal course.

BACKGROUND: Carcinoma of the upper respiratory tract is rare in childhood, and cytogenetic aberrations have not been characterized in this population. The chromosomal translocation 15;19 has been reported four times previously. All patients were young and had tumors arising in the thorax. The three reports that provide clinical follow-up all describe superior vena cava syndrome and death soon after presentation. All tumors were diagnosed as carcinoma (three undifferentiated, one mucoepidermoid), and the authors suggested thymus, lung, or germ cell origin. METHODS: The authors investigated the clinical and pathologic findings in two patients with poorly differentiated carcinoma showing evidence of t(15;19). This included a 13-year-old girl with a rapidly growing epiglottic mass, leading to superior vena cava syndrome and death and a 12-year-old girl with an aggressive nasopharyngeal mass showing intracranial extension. RESULTS: The laryngeal tumor was poorly differentiated, with vesicular nuclei, prominent nucleoli, extensive necrosis, and a lymphoplasmacytic infiltrate; cells were positive for cytokeratin and negative for lymphoma, melanoma, germ cell, and endocrine markers. Electron microscopy showed rare intermediate junctions and basal lamina. The nasopharyngeal tumor was poorly differentiated with areas of obvious squamous differentiation observed histologically, immunophenotypically, and ultrastructurally. Cytogenetic and fluorescent in situ hybridization studies were consistent with t(15;19)(q13;p13.1) in both cases. Both children received chemo- and radiotherapy. The first child died of disease after 36 weeks; autopsy revealed tumor in the larynx with spread to the skin/subcutis (neck and thorax) and lymph nodes (cervical, subcarinal, and pulmonary hilar). The second child developed widespread bony metastases and died of disease after 13 weeks. CONCLUSIONS: In conjunction with previous reports, the authors' findings show that t(15;19) is part of a distinct clinicopathologic entity characterized by young age, midline carcinoma of the neck or upper thorax, and a rapidly fatal course. Female gender and superior vena cava syndrome are common. The histogenesis of these distinctive tumors is unknown. The authors' findings suggest origin in the upper airway, perhaps from submucosal glands.

A simple method for assessing exposure to internal emitters.

One of the most challenging aspects of regulatory compliance can be demonstrating compliance with internal dosimetry requirements. For long-lived alpha-emitting radionuclides in particular, the sensitivity and accuracy of bioassay analysis and whole body counting may not allow for adequate assessment of intakes. Simple and effective measures can be used to control the workplace for the internal hazards associated with long-lived radioactive material using methods that measure directly the air to which workers are exposed. This paper provides an easy assessment tool that uses direct measurement of the specific activity of dusts in breathing zone air to evaluate internal exposures. Using this method, sensitive assessments can be made to determine if intakes are likely to have occurred and, if so, at what magnitude. It is not a substitute for confirmatory bioassay or whole body counting but a simple method to evaluate expectations for internal exposures.